How mixed chimerism can free transpant recipients from immunosuppression
In literature, a "chimera" is a creature from Greek mythology that is made of parts from different animals. Perhaps the most famous chimera is "Cerberus," the part dog, part snake who was captured by Hercules in his final labor.
In immunology, a chimera refers to an immune system consisting of cells from different individuals. And with the success of his ITN trial, that resulted in 4 patients who have been completely free from all immunosuppressive drugs for up to 5 years, the most famous chimera-creating immunologist is now ITN principal investigator Dr. David Sachs.
In theory, the procedure is relatively simple - at the same time as a kidney transplant, also include some bone marrow from the same donor. The result is an immune system that is a mix of the donor and recipient. As shown at right, the cells of each person's immune system that are primed to attack "foreign cells", will attack each other, cancelling each other out as they mature in the thymus. What is left is a mixture of mature donor and recipient immune cells that are not programmed to react to each other - or the newly transplanted kidney. Therefore, no anti-rejections medicines required.
In practice, the technique is not nearly so simple. First, the transplant recipient's bone marrow must be partially destroyed to make room for the recipient's marrow, using cytotoxic drugs often used for cancer treatment. Then, other drugs reduce the patient's supply of T cells, which are implicated in transplant rejection. Finally, the donor kidney, as well as some of the donor's bone marrow are transplanted. Recipients must be confined in a sterile environment for a short time following the procedure to prevent infection while their immune system rebuilds.
The ITN-sponsored study showed that the theory was essentially correct and immune tolerance was established in 4 of 5 of his patients. A mystery remains, however - in the successful patients, this mixed state of chimerism lasted only for a short time after the transplant. Now, the challenge is to find out why it was only temporary and how such temporary chimerism can still create immune tolerance.
Still, it is a remarkable accomplishment for Dr. Sachs and his team, a tremendous success for the ITN and a watershed moment for the field of transplantation. To underscore the significance of this achievement, consider that transplant tolerance is often referred to as the "holy grail" of immunology.
The reason that it is important is two-fold. First, although immunosuppressive drugs have greatly reduced the risk of rejecting a kidney transplant in the short-term, long-term risk has not improved as much. It is hoped that tolerance will be much more durable and will impact the long-term transplant survival. Second, the immunosuppressive drugs themselves are fraught with side effects, including increasing the risk of life-threatening infections and certain cancers.
This breakthrough study was one of the first transplant protocols approved by the ITN in October 2000. A follow-up study with Dr. Sachs is now being planned that will aim to treat a larger number or patients with end-stage kidney disease.